This invention is generally in the field of anesthesiology and, in particular, the restoration and/or boosting of a previously administered local anesthesia by the use. of a non-local anesthetic agent to reactivate and/or prolong local anesthesia.
Methods and/or formulations heretofore used to provided localized anesthesia are advantageously reversible so that nerve conduction and motor and/or sensory function returns. However, in many situations it becomes necessary to repeat the same local anesthesia one or more additional times in order to protect a patient from chronic pain or from pain induced by repeated surgical or medical procedures.
In order to provide local and/or anesthesia for extended periods, clinicians currently use local anesthetic agents administered through a catheter or syringe to a site where anesthesia is to be induced. Thus, prolonged local anesthesia, over a period of greater than about 6 hours, has heretofore required that local anesthetic be administered either as a bolus or through an indwelling catheter connected to an infusion pump. Similarly, heretofore, reactivation of local anesthesia has required repeated administered of a local anesthetic through an indwelling catheter or by reinjection. These methods have the disadvantage of potentially causing irreversible damage to nerves or surrounding tissues due to fluctuations in local anesthetic concentration and in the accumulation and diffusion of potentially toxic levels of local anesthetic into the systemic circulation.
One approach to this problem is to provide for a prolonged, sustained local anesthesia, as is disclosed by WO 94/05265. This published international patent application describes improved biocompatible controlled release systems consisting of a polymeric matrix incorporation of a local anesthetic for the prolonged administration of the local anesthetic agent. The devices are selected on the basis of their degradation profiles: release of the local anesthetic in a linear, controlled manner over the period of preferably two weeks and degradation in vivo with a half-life ranging from less than six months to about a year and more, and preferably from about two to four weeks, to induce localized anesthesia. The anti-inflammatories that are said to be useful include steroids such as dexamethasone, cortisone, prednisone, and others routinely administered orally or by injection. The exemplified pellet formulations comprise only about 20% local anesthetic and this published international patent application teaches that the selection of the polymers is critical to providing a sustained release of the local anesthetic agent. This publication also teaches that the anti-inflammatory agent serves to prevent localized tissue inflammation and encapsulation of the injection site with a connective tissue capsule. However, the local anesthesia so provided is of necessity prolonged, without any option for modulating the level of anesthesia.
Local anesthetic agents have been incorporated into biocompatible polymeric devices, such as, for example, polylactic acid microspheres, as described by Wakiyama, et al., Chem. Pharm. Bull., 30:3719-3727 (1982). In contrast to the lipid based materials, the poly(lactic acid) devices take over a year to degrade and cause localized inflammation. Berde, et al., Abstracts of Scientific Papers, 1990 Annual Meeting, Amer. Soc. Anesthesiologists, 73:A776 (September 1990), reported the use of a device formed of a polyanhydride polymer matrix of copolymer 1,3 bis(p-carboxyphenoxy)propane and sebacic acid, in a ratio of 1:4, into which dibucaine free base was incorporated by compression molding. This drug-polymer device, however, had several drawbacks. For example, because the drug was incorporated into the polymer matrix by compression molding, the device sometimes displayed bulk erosion, causing fast initial release of drug.
Nevertheless, heretofore there has been no method or formulations known to the art for reactivating, prolonging or otherwise boosting a previously administered local anesthesia without the use of repeated dose of a local anesthetic.
Accordingly, it is an object of the present invention to provide methods and compositions for modulating local anesthesia by administering one or more glucocorticosteroid agents (also referred to herein as glucocorticoid agents) before, simultaneously with or after the administration of a local anesthetic at a site in a patient. It is a further object of the present invention to provide methods and compositions that are able to reactivate or prolong local anesthetic activity that has previously diminished or worn off
It is a still further object of the present invention to provide methods and compositions for modulating the degree of local anesthesia wherein the active restorative or prolonging agents are pharmaceutically acceptable glucocorticosteroids that are locally or systemically administered to a patient needing or desiring to restore a previously induced local anesthesia.
In accordance with the above-mentioned objects and others, the invention is related to methods and compositions for reactivating and/or prolonging a local anesthetic effect, that has previously been induced by an implanted or injected local anesthetic formulation.
Accordingly, the present invention broadly provides methods for reactivating and/or prolonging an induced local anesthesia at a site in a patient in need thereof, comprising administering to the patient at a site at which local anesthesia was previously induced, a pharmaceutically acceptable composition that includes a glucocorticosteroid in an amount effective to reactivate and/or prolong the previously induced local anesthesia. The previous local anesthesia is induced by any art known local anesthetic or by a combination of any suitable art-known local anesthetic and any suitable art-known glucocorticosteroid.
The glucocorticosteroid for reactivating and/or prolonging a local anesthesia is administered by, e.g., systemic administration, e.g., orally or intravenously, or by implantation, infiltration, injection and/or infusion at or adjacent to the site requiring reactivated or prolonged anesthesia, and is administered, for example, before or after the local anesthesia has substantially worn off, to provide reactivation and/or prolongation of the effect. At least a portion of the glucocorticoid is administered, simply by way of example, at a time ranging from about 1 to about 72 hours or more, from about 1 to about 36 hours, from about 1 to about 24 hours, from about 1 to about 12 hours, from about 1 to about 6 hours, and from about 1 to about 4 hours, or from about 4 to about 72 hours and from about 4 to about 24 hours, after the time that the (e.g., first) local anesthetic was administered.
The previously administered local anesthetic is, for example, bupivacaine, ropivacaine, dibucaine, procaine, chloroprocaine, prilocaine, mepivacaine, etidocaine, tetracaine, lidocaine, xylocaine, and salts thereof or any other pharmaceutically acceptable art-known local anesthetic or mixtures thereof. The glucocorticosteroid is, e.g., dexamethasone, cortisone, prednisone, hydrocortisone, beclomethasone dipropionate, betamethasone, flunisolide, methylprednisone, paramethasone, prednisolone, triamcinolone, alclometasone, amcinonide, clobetasol, fludrocortisone, diflorasone diacetate, fluocinolone acetonide, fluocinonide, fluorometholone, flurandrenolide, halcinonide, medrysone and mometasone and pharmaceutically acceptable mixtures thereof and salts thereof or any other suitable art-known glucocorticosteroid, either naturally occurring or synthetic.
In the method according to the invention, at least a portion of the glucocorticosteroid may be administered systemically, e.g., orally or by systenmic injection, but is preferably administered locally at the desired site in a patient. The locally administered glucocorticosteroid can be administered in immediate release form, in controlled release form or in both immediate release and controlled release form. The immediate release and/or controlled release forms are preferably prepared in a form suitable for injection, infusion and/or application in a pharmaceutically acceptable medium, e.g., as a solution, suspension or even, e.g., as a plurality of microspheres incorporating one or more agents, including a glucocorticosteroid. When controlled release microspheres are provided, at least a portion of the glucocorticosteroid is optionally in immediate release form in the injection medium.
The methods according to the present invention provide a local anesthesia prolonged by reactivation of a previously administered local anesthetic agent, the reactivation providing a local anesthesia having a duration ranging from, e.g., about 1.1 to about 14 fold, or more, of the duration of local anesthesia induced by controlled release local anesthetic without glucocorticosteroid enhancement. In a preferred embodiment, the methods, the prolongation ranges from about 6 to about 13 fold of the duration of local anesthesia induced by controlled release local anesthetic without glucocorticosteroid enhancement. The methods according to the invention are therefore capable of providing an initial period of local anesthetic induced anesthesia, that is either prolonged or that is reactivated to provide a local anesthesia with a duration ranging from about 1 to about 72 hours or more, from about 1 to about 36 hours, from about 1 to about 24 hours, from about 4 to about 8 hours and from about 1 to about 2 hours, measured from the time of administration of the reactivating composition.
Further, the invention also provides pharmaceutical formulations for providing a regional local anesthesia in a patient that, when administered to a local site in a patient, sequentially releases an effective amount of a pharmaceutically acceptable local anesthetic and then at a time after administration, releases an amount of a glucocorticosteroid effective to reactivate and/or prolong the local anesthesia. Such a pharmaceutical formulation according to the invention also includes an effective amount of a biocompatible, controlled release material effective to prolong the release of said local anesthetic from said formulation and effective to delay the release of the glucocorticosteroid for a desired time after administration. Simply by way of example, the glucocorticoid agent according to the invention can be released or administered at the desired site at any time, but preferably at least a portion that is effective to prolong and/or reactivate the desired local anesthesia is released or administered after the local anesthetic has been administered. At least a portion of the glucocorticoid is released from said formulation, simply by way of example, at a time ranging from about 1 to about 72 hours or more, from about 1 to about 36 hours, from about 1 to about 24 hours, from about 1 to about 6 hours, or from about 4 to about 24 hours and from about 1 to about 2 hours, measured from the time that the (e.g., first) local anesthetic was administered.
While any pharmaceutically acceptable controlled release material may be employed, the pharmaceutically acceptable controlled release materials preferably are prepared from a polymer such as, for example, polyanhydrides, copolymers of lactic acid and glycolic acid, poly(lactic) acid, poly(glycolic) acid, polyesters, polyorthoesters, proteins and/or polysaccharides.
A pharmaceutically acceptable local anesthetic is, for example, ropivacaine, bupivacaine, dibucaine, etidocaine, tetracaine, lidocaine, xylocaine, mixtures thereof, and salts thereof and others well known to the art. The local anesthetic is incorporated into the controlled release formula at a weight percent ranging from about 0.1 to about 90%
A pharmaceutically acceptable glucocorticosteroid. includes, e.g., dexamethasone, cortisone, prednisone, hydrocortisone, beclomethasone dipropionate, betamethasone, flunisolide, methylprednisone, paramethasone, prednisolone, triamcinolone, alclometasone, amcinonide, clobetasol, fludrocortisone, diflorasone diacetate, fluocinolone acetonide, fluocinonide, fluorometholone, flurandrenolide, halcinonide, medrysone and/or mometasone and pharmaceutically acceptable mixtures salts thereof or any other suitable glucocorticosteroid known to the art. Preferably, dexamethasone is used.
The pharmaceutically acceptable formulation according to the invention provides a reactivated local anesthesia of a duration ranging from about 1.1 to about 14 fold, or more, of the duration of local anesthesia induced by controlled release local anesthetic without glucocorticosteroid enhancement. In a preferred embodiment, the methods, the prolongation ranges from about 6 to about 13 fold of the duration of local anesthesia induced by controlled release local anesthetic without glucocorticosteroid enhancement. The methods and formulations according to the invention are therefore capable of providing an initial period of local anesthetic induced anesthesia, followed by a second period of anesthesia, that is either prolonged or that is reactivated to provide a second period of local anesthesia.